PROJECT SUMMARY Cancer is a critical problem in immunosuppressed patients, particularly, who receive organ transplants; and kidney/renal cancer is one of the major cancers in these patients. Direct tumorigenic pathways (independent of immune escape mechanism) can play crucial roles in the development of post-transplantation cancer. c-Met is a receptor tyrosine kinase, which is significantly over-expressed in renal cancer. It can induce tumor growth by modulating the redox pathway, angiogenesis and apoptotic events, through the regulation of cytoprotective molecules Nrf2 and heme oxygenase-1 (HO-1). Nrf2/HO-1 has been shown to modulate the redox state of cancer cells (by detoxification of reactive oxygen species, ROS), and to protect them from chemotherapeutic drug-induced apoptosis. Interestingly, the c-Met-Nrf2-HO-1 pathway is also activated during the post- transplantation period. The mTOR inhibitor RAPA is used in transplant patients to prevent organ rejection; and interestingly, it also has anti-angiogenic potential, and is used for the treatment of renal cancer. However, the RAPA responses are short lived, and most of the patients finally develop resistance. Prolonged RAPA treatment cannot prevent post-transplantation cancer due to the activation of Akt by relieving the inhibitory loop. Thus, new therapeutic approach needs to be developed for kidney cancer. Honokiol (C18H18O2), a novel agent (isolated from Magnolia obovata), is being tested in pre-clinical models for its anti-tumorigenic potential. In addition, Honokiol also has anti-inflammatory property, which can be utilized for the treatment of transplant patients to sustain their immune suppression. In preliminary studies, we have observed that Honokiol treatment can down-regulate c-Met-induced Ras activation (having cross-talk with Akt-mTOR) and inhibit Nrf2/HO-1 in renal cancer cells. Together, Honokiol appears to be a promising therapeutic agent for c-Met-induced post- transplantation renal cancer. We hypothesize that a combination therapy using Honokiol and the mTOR inhibitor RAPA will not only prolong allograft survival, but also prevent c-Met-induced and Nrf2/HO-1-mediated post-transplantation renal cancer. In the specific aims, we will: 1) study the mechanism(s) by which Honokiol inhibits c-Met-induced tumorigenic signals in renal cancer cells through destabilization/inactivation of Nrf2/HO- 1 and regulation of the redox pathway (Aim-1), 2) examine how Honokiol treatment in the presence of mTOR inhibitor RAPA can down-regulate c-Met-induced pathways for renal cancer growth and progression in vitro, and in a tumor xenograft model (Aim-2), and 3) test the effect of Honokiol and RAPA combination therapy in preventing early renal tumorigenesis and c-Met-induced post-transplantation renal cancer using novel murine models (Aim-3). Our studies should lead to a paradigm shift to identify a novel combination therapy with Honokiol to prolong allograft survival as well as to prevent c-Met-induced post-transplantation cancer.